Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3
Skeletal muscle contractions are initiated by an increase in Ca2+ released during excitation–contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule m...
Saved in:
Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 2; pp. E228 - E236 |
---|---|
Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
10.01.2017
|
Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Skeletal muscle contractions are initiated by an increase in Ca2+ released during excitation–contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3NAM
myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+. These findings define critical roles for Stac3 in EC coupling and human disease. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed by Clara Franzini-Armstrong, November 23, 2016 (sent for review July 25, 2016; reviewed by Derek R. Laver and Jerome Parness) 1I.-U.H., L.G., V.Y., and C.F.-A. contributed equally to this work. Author contributions: J.W.L., R.T.D., and J.Y.K. designed research; J.W.L., I.-U.H., L.G., V.Y., M.L., E.J.H., W.W., and C.F.-A. performed research; J.W.L., I.-U.H., and D.L. contributed new reagents/analytic tools; J.W.L., I.-U.H., L.G., V.Y., D.L., C.F.-A., R.T.D., and J.Y.K. analyzed data; and J.W.L., C.F.-A, and J.Y.K. wrote the paper. Reviewers: D.R.L., University of Newcastle; and J.P., Children’s Hospital of Pittsburgh. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1619238114 |